We propose to use unprecedented longitudinal data to define typical and atypical neurodevelopmental trajectories and to study the role of exposures to psychoactive substances and other environmental factors in variations in structural and functional brain development from early childhood through adolescence. Using a unique prospective cohort sample of children whose mothers were first studied during pregnancy, trajectories of brain development will be constructed using longitudinal data from 4000 adolescents participating in the Dutch Generation R (GenR) Study. The GenR cohort was ascertained during gestation and has been assessed repeatedly through 11 years of age to date, including MRI data collection. GenR is uniquely able to provide data to construct trajectories of brain development and to determine if prenatal and early exposures have lasting impacts on neurodevelopment through adolescence. In addition, we can determine if adolescent use of psychoactive substances perturbs neurodevelopment through adolescence in ways that are related to adaptive functioning. Because the inherently non-linear nature of typical and atypical brain- and behavioral development, they can only be understood using longitudinal data. The children have already been assessed through childhood and we will conduct two additional assessment waves during early and late adolescence to continue to map neurodevelopmental trajectories and to study potential variations of these trajectories linked to environmental exposures. Our emphasis will be on the association of trajectories of neurodevelopment with (a) prenatal exposures to psychoactive substance and environmental toxicants during pregnancy, and (b) the use of psychoactive substances by adolescents in the same individuals. To fully understand these exposures, we will evaluate their role in neurodevelopment in the context of a broad range of exposures to the nutritional and social environment. This will allow us to build a comprehensive model of the trajectories of brain development in the context of the child and adolescent?s past and changing environments. Individual differences in trajectories of neurodevelopment will be related to substance use disorders, psychopathology, and adaptive functioning in adolescence. Sex-by-exposure interactions will be tested to ensure that findings are not obscured by sex differences. We will examine resilience in the face of environmental exposures by determining if social and nutritional factors moderate these associations. We will test hypotheses regarding the mediation of exposure-outcome associations by variations in brain structure and function. We will use formal transportability models to validly generalize findings from the GenR cohort to the U.S. All data will be anonymized and shared with the research community in an open science format. 1 UG3 DA 045251-01